Aromatic compounds, pharmaceutical compositions thereof and uses

Abstract

The present application discloses the use of an aromatic compound and its pharmaceutical composition, a pharmaceutical composition containing the compound, and a preparation method of such a compound and its intermediate. The present application also discloses the pharmaceutical use of the compound for preparing a drug for preventing or treating liver diseases and / or diseases or disorders related to bile duct diseases.

Description

[0001] This application is based on an application with CN application number 202010130024.4 and a filing date of February 28, 2020, and claims its priority. The disclosure of this CN application is hereby incorporated herein by reference in its entirety. Technical Field

[0002] This application belongs to the pharmaceutical field, and particularly relates to a class of aromatic compounds, pharmaceutical compositions containing such compounds, and preparation methods of such compounds and their intermediates. This application also relates to the use of such compounds for the preparation of drugs for preventing or treating diseases or disorders related to peroxisome proliferator-activated receptor (PPAR). Background Art

[0003] Non-alcoholic fatty liver disease (NAFLD) is a clinical and pathological syndrome with histological changes in the liver similar to those of alcoholic liver disease but without a history of excessive alcohol consumption, including simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH), and its associated cirrhosis. Among them, NASH is an important intermediate stage in the progression of NAFLD. With the high incidence of insulin resistance and its associated multiple metabolic syndromes, the prevalence of NAFLD / NASH is gradually increasing. In developed countries and regions, NAFLD has now become one of the most common liver diseases. The prevalence of NAFLD in the general adult population in the United States is 10 - 40% (average 20%), and that of NASH is 2 - 5% (average 3%). The prevalence of NAFLD is even higher in special populations such as the obese, diabetics, and those with chronic elevation of serum alanine aminotransferase (ALT), and the onset of NAFLD is gradually becoming younger.

[0004] In addition to directly leading to decompensated cirrhosis, hepatocellular carcinoma, and recurrence in transplanted livers, non-alcoholic fatty liver disease can also affect the progression of other chronic liver diseases and participate in the pathogenesis of type 2 diabetes and atherosclerosis. Metabolic syndrome-related malignancies, arteriosclerotic cardio-cerebrovascular diseases, and cirrhosis are important factors affecting the quality of life and life expectancy of patients with non-alcoholic fatty liver disease. Currently, NASH has become one of the important pre-cirrhotic lesions second only to chronic viral hepatitis and alcoholic liver disease and is a common cause of abnormal serum transaminases in the health examination population. Effective prevention and treatment of NASH are expected to prevent the progression of chronic liver diseases and reduce the occurrence of cirrhosis and liver disease-related disabilities and deaths. Non-alcoholic fatty liver disease is a new challenge in the field of contemporary medicine, and the development of drugs for treating non-alcoholic fatty liver-related diseases has important clinical significance.

[0005] The peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor transcription factor superfamily and plays a key role in regulating metabolic homeostasis, inflammation, cell growth, and differentiation. PPAR agonists are used as lipid-lowering agents and oral hypoglycemic agents in type II diabetes. In recent years, studies have found that such agonists have hepatoprotective functions. PPARα is highly expressed in hepatocytes and mainly regulates fatty acid transport and β-oxidation. In addition, PPARα can also regulate gluconeogenesis and inflammatory responses. Similar to PPARα, PPARδ can regulate glucose utilization and lipoprotein metabolism in the liver and has significant anti-inflammatory activity. Based on the studies of the functions of PPARα and PPARδ, PPAR agonists have the potential to solve various biological problems involved in the pathogenesis of NASH, or more broadly, metabolic and cardiovascular problems. Summary of the Invention

[0006] The present application provides compounds containing a 2-phenoxyacetic acid structure as PPAR agonists, especially those with excellent dual agonistic activity against PPARα&δ, better physicochemical properties (such as solubility, physical and / or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, appropriate half-life, and duration of action), and / or improved safety (lower toxicity and / or fewer side effects, wider therapeutic window) and other more excellent properties.

[0007] In one aspect, the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of general formula (I):

[0008]

[0009] Wherein:

[0010] R 1 、R 2 、R 3 、R 4 、R 5 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylthio; or, R 1 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, R 3 、R 4 、R 5Each independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylthio;

[0011] X is -CH2CH2-;

[0012] Y is selected from -(CR 6 R 6 ')- and -C(=N-OR 7 );

[0013] R 6 and R 6 ' each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl and aryloxy;

[0014] R 7 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl and aryl;

[0015] The ring A linked to Y is selected from:

[0016]

[0017] R 8 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl;

[0018] n is any integer from 0 to 6.

[0019] In another aspect, the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, prodrug or a mixture thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or gaseous preparation.

[0020] In another aspect, the present application provides a kit product comprising the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, prodrug or a mixture thereof, or the pharmaceutical composition described herein, and optionally a package insert.

[0021] Another aspect of the present application provides the use of the compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or a mixture thereof, pharmaceutical composition, or kit product in the preparation of a drug for preventing or treating a PPAR-related disease or disorder.

[0022] Another aspect of the present application provides the compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or a mixture thereof, pharmaceutical composition, or kit product for preventing or treating a PPAR-related disease or disorder.

[0023] Another aspect of the present application provides a method for preventing or treating a PPAR-related disease or disorder, which comprises administering to a subject in need thereof an effective amount of the compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug or a mixture thereof, pharmaceutical composition, or kit product.

[0024] In another aspect, the present application provides the use of the compound described herein or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or the pharmaceutical composition described herein as a reagent for activating PPAR in cells.

[0025] In another aspect, the present application provides the compound described herein or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or the pharmaceutical composition described herein for activating PPAR in cells.

[0026] In another aspect, the present application provides a method for activating PPAR in cells, which comprises the step of contacting the cells with an effective amount of the compound described herein or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or the pharmaceutical composition described herein.

[0027] Definition

[0028] Unless otherwise defined herein, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques as commonly understood in the art, including variations of those techniques or substitutions of equivalent techniques that are obvious to one of ordinary skill in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the present invention.

[0029] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12 carbon atoms, such as 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 alkyl" refers to a linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (such as halogen) (in which case the group is referred to as "haloalkyl") (for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon group having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0030] As used herein, the term "cycloalkyl" or "cycloalkanyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (for example, a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring containing 3 to 6 ring-forming carbon atoms (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0031] As used herein, the term "alkoxy" refers to an alkyl-O- group, where the alkyl is as described above. The alkoxy group can contain 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy and isopropoxy. The alkyl of the alkoxy group is connected to the adjacent moiety through an oxygen atom.

[0032] As used herein, the term "alkylthio" refers to an alkyl-S-group, wherein the alkyl is as described above. C 1-6 Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.

[0033] As used herein, the terms "heterocyclic group" and "heterocycloalkyl" refer to saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic groups having 3 to 6 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C. For example, "3-6 membered heterocycloalkyl" is a saturated or partially unsaturated heterocyclic group having 2 to 5 (such as 2, 3, 4, or 5) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. Examples of heterocycloalkyl include, but are not limited to: oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. The heterocycloalkyl may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0034] As used herein, the term "aryl" refers to a monocyclic or fused-ring polycyclic aromatic group of all carbon atoms having a conjugated π electron system. For example, the term "C 6-14 aryl" means an aromatic group containing 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.).

[0035] As used herein, the term "aryloxy" refers to an -O-aryl group, wherein the aryl is as described above. For example: -O-phenyl, etc.

[0036] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the specified atom are replaced by a selection from the indicated groups, provided that the normal valence of the specified atom in the current case is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are only permitted when such combinations form a stable compound.

[0037] If a substituent is described as “optionally substituted with...”, the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced by independently selected optional substituents, either singly and / or together. If a nitrogen of a substituent is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced by an independently selected optional substituent.

[0038] If a substituent is described as “independently selected from” a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0039] As used herein, the term “one or more” means 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, or 10.

[0040] Unless specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0041] When the bond of a substituent is shown as passing through a bond connecting two atoms in a ring, such a substituent may be bonded to any ring-forming atom in the ring that is capable of being substituted.

[0042] This application also relates to pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds described herein except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominating in nature. Examples of isotopes suitable for inclusion in the compounds described herein include (but are not limited to) isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (e.g., 11 C, 13 C and 14 C); isotopes of chlorine (e.g., 36 Cl); isotopes of fluorine (e.g., 18 F); isotopes of iodine (e.g., 123 I and 125 I); isotopes of nitrogen (e.g., 13 N and 15 N); isotopes of oxygen (e.g., 15 O, 17 O and 18 O); isotopes of phosphorus (e.g., 32 P); and isotopes of sulfur (e.g., 35 S).

[0043] The term "stereoisomer" refers to isomers formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, it can give rise to racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds described herein can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0044] In this article, solid lines can be used solid wedges or dashed wedges to depict the covalent bonds of the compounds. Using a solid line to depict a bond attached to an asymmetric carbon atom is intended to indicate all possible stereoisomers including at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.). Using a solid or dashed wedge to depict a bond attached to an asymmetric carbon atom is intended to indicate the presence of the depicted stereoisomer. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds are intended to exist in the form of stereoisomers which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds described herein can exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0045] This article also relates to all possible crystalline forms or polymorphs of the compounds, which can be a single polymorph or a mixture of any proportion of more than one polymorph.

[0046] It should also be understood that certain compounds herein can exist in free form for treatment or, when appropriate, in the form of their pharmaceutically acceptable derivatives. The pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which can directly or indirectly provide the compounds described herein or their metabolites or residues after administration to a patient in need thereof. Accordingly, when referring to "the compounds described herein" in this article, it is also intended to cover the above various derivative forms of the compounds.

[0047] Pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts thereof.

[0048] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts.

[0049] A review of suitable salts can be found in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0050] As used herein, the term “ester” means an ester derived from each of the general formula compounds of the present application, which includes physiologically hydrolysable esters (which can be hydrolysed under physiological conditions to release the compounds described herein in the form of the free acid or alcohol). The compounds described herein can themselves also be esters.

[0051] The compounds described herein can exist in the form of solvates (preferably hydrates), wherein the compound contains a polar solvent, particularly for example water, methanol or ethanol, as a structural element of the compound lattice. The amount of the polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric ratios.

[0052] Those skilled in the art will understand that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to be oxidized to an oxide; those skilled in the art will identify the nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W.H. Cheeseman and E.S.G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0053] This application also relates to metabolites of the compounds, i.e., substances formed in vivo upon administration of the compounds. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, etc. of the administered compound. Accordingly, this application also relates to metabolites of the compounds, including compounds prepared by a method of contacting the compound with a mammal for a time sufficient to produce its metabolites.

[0054] This application further relates to prodrugs of the compounds, which are certain derivatives of the compounds that may have little or no pharmacological activity by themselves and can be converted into the compounds with the desired activity by, for example, hydrolytic cleavage when administered to or on the body. Generally, such prodrugs will be functional group derivatives of the compounds and are easily converted into the desired therapeutic active compounds in vivo. Other information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs can be prepared, for example, by replacing appropriate functional groups present in the compounds with certain moieties known to those skilled in the art as "pro-moieties" (such as those described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0055] This application also relates to the compounds containing protecting groups. In any process for preparing the compounds, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any relevant molecules, thereby forming chemically protected forms of the compounds. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Using methods known in the art, the protecting groups can be removed at appropriate subsequent stages.

[0056] The term "about" means within ±10% of the stated value, preferably within ±5% of the stated value, more preferably within ±2% of the stated value. Detailed Description

[0057] Compound

[0058] In some embodiments, this application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound has a structure of general formula (I):

[0059]

[0060] Wherein:

[0061] R 1 、R 2 、R 3 、R4 , R 5 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylthio; or, R 1 and R 2 together with the carbon atom to which they are attached form C 3-6 cycloalkyl, R 3 , R 4 , R 5 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylthio;

[0062] X is -CH2CH2-;

[0063] Y is selected from -(CR 6 R 6 ')- and -C(=N-OR 7 );

[0064] R 6 and R 6 ' are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl and aryloxy;

[0065] R 7 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl and aryl;

[0066] The ring A attached to Y is selected from:

[0067]

[0068] R 8 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl;

[0069] n is any integer from 0 to 6.

[0070] In some embodiments, the present application provides a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,

[0071]

[0072] Wherein, R 1 、R 2 、R 3 、R 4 、R 5 、ring A and n are as defined in general formula (I).

[0073] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, R 1 、R 2 、R 3 、R 4 and R 5 are each independently selected from H, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylthio; or, R 1 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, and R 3 、R 4 and R 5 are each independently selected from H, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylthio.

[0074] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, R 1 、R 2 、R 3 、R 4 、R 5 are each independently selected from H, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, C 1-4 alkoxy and C 1-4 alkylthio.

[0075] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, R 1 and R 2 are methyl; R 3 and R 4 are each independently selected from methyl and chlorine; each R 5 is independently selected from H, chlorine, methyl, methoxy and methylthio.

[0076] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, R 1 、R 2 、R 3 and R 4 are methyl; each R 5 is independently selected from H, chlorine, methyl, methoxy and methylthio.

[0077] In some embodiments, in the compounds of formula (I) or formula (II) provided by the present application, n is 0, 1, 2 or 3.

[0078] In some embodiments, in the compounds of formula (I) or formula (II) provided by the present application, n is 1 or 2.

[0079] In some embodiments, in the compound of formula (I) provided by the present application, Y is -(CR 6 R 6 ’)-, R 6 and R 6 ’ are defined as described above; preferably, R 6 and R 6’ are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, -OH, -OC 1-4 alkyl, -OC 3-6 cycloalkyl and aryloxy; preferably, R 6 is H; R 6‘ is selected from -OH and -OC 1-4 alkyl; more preferably, R 6 is H; R 6 ‘ is -OH.

[0080] In some embodiments, in the compound of formula (I) provided by the present application, Y is -CH(OH)-.

[0081] In some embodiments, in the compound of formula (I) provided by the present application, Y is -C(=N-OR 7 )-, R 7 is defined as described above; preferably, R 7 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and aryl (such as C 6-10 aryl); preferably, R 7 is selected from H and C 1-4 alkyl; more preferably, R 7 is H.

[0082] In some embodiments, in the compounds of formula (I) or formula (II) provided by the present application, R 8 is selected from H, C 1-4 alkyl and C 3-6 cycloalkyl.

[0083] In some embodiments, in the compounds of formula (I) or formula (II) provided by the present application, R 8 is H or methyl.

[0084] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, R 8 is H.

[0085] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, ring A connected to Y is selected from:

[0086]

[0087] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, is selected from:

[0088]

[0089] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, is selected from:

[0090]

[0091] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, is selected from:

[0092]

[0093] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, the one connected to Y is selected from:

[0094]

[0095] wherein, R 8 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl; preferably, R 8 is H or methyl; more preferably, R 8 is H.

[0096] In some embodiments, in the compound of formula (I) or formula (II) provided by the present application, is selected from:

[0097] R 1 and R 2 are methyl; R 3 and R 4 each independently is selected from methyl and chlorine; each R 5 is independently selected from H, chlorine, methyl, methoxy and methylthio.

[0098] In some embodiments, among the compounds of formula (I) or formula (II) provided by the present application, selected from:

[0099] R 1 and R 2 is methyl; R 3 and R 4 are each independently selected from methyl and chlorine.

[0100] The compounds cover the compounds obtained by any combination of each embodiment.

[0101] In some embodiments, the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound is selected from:

[0102]

[0103]

[0104] In some preferred embodiments, the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound:

[0105]

[0106] In some embodiments, the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound:

[0107]

[0108] The present application also relates to the stereoisomers of the following compounds:

[0109]

[0110] In some embodiments, the stereoisomer has a left-handed optical rotation direction detected under the following optical rotation detection conditions: detection temperature: 20 °C, detection wavelength 589.3 nm, solvent is methanol, and concentration is 100 mg / mL. In some embodiments, the specific rotation [α] of the stereoisomer D 20 =-9.5°±1°. In some embodiments, the specific rotation [α] of the stereoisomer D 20-9.5° ± 0.9°, -9.5° ± 0.8°, -9.5° ± 0.7°, -9.5° ± 0.6°, -9.5° ± 0.5°, -9.5° ± 0.4°, -9.5° ± 0.3°, -9.5° ± 0.2°, or -9.5° ± 0.1°. In some embodiments, the retention time of the stereoisomer under the following liquid phase conditions is 5.8 min ± 1 min, e.g., 5.8 min ± 0.9 min, 5.8 min ± 0.8 min, 5.8 min ± 0.7 min, 5.8 min ± 0.6 min, 5.8 min ± 0.5 min, 5.8 min ± 0.4 min, 5.8 min ± 0.3 min, 5.8 min ± 0.2 min, or 5.8 min ± 0.1 min:

[0111] Column: CHIRALPAK IC (IG00CD-KJ016);

[0112] Column size: 0.46 cm I.D. × 15 cm L;

[0113] Sample volume: 1 μL;

[0114] Mobile phase: Hexane / EtOH / HAC = 85 / 15 / 0.1 (V / V / V);

[0115] Flow rate: 1.0 ml / min;

[0116] Detection wavelength: UV 254 nm; and

[0117] Column temperature: 35 °C.

[0118] In some other embodiments, the optical rotation direction of the stereoisomer detected under the following optical rotation detection conditions is dextrorotatory: Detection temperature: 20 °C, detection wavelength 589.3 nm, solvent is methanol, concentration is 100 mg / mL. In some embodiments, the specific rotation [α] of the stereoisomer D 20 = +9.7° ± 1°. In some embodiments, the specific rotation [α] of the stereoisomer D 20It is +9.7°±0.9°, +9.7°±0.8°, +9.7°±0.7°, +9.7°±0.6°, +9.7°±0.5°, +9.7°±0.4°, +9.7°±0.3°, +9.7°±0.2° or +9.7°±0.1°. In some embodiments, the retention time of the stereoisomer under the following liquid phase conditions is 3.5 min±1 min, for example, 3.5 min±0.9 min, 3.5 min±0.8 min, 3.5 min±0.7 min, 3.5 min±0.6 min, 3.5 min±0.5 min, 3.5 min±0.4 min, 3.5 min±0.3 min, 3.5 min±0.2 min or 3.5 min±0.1 min:

[0119] Column: CHIRALPAK IC (IG00CD-KJ016);

[0120] Column size: 0.46 cm I.D.×15 cm L;

[0121] Sample injection volume: 1 μL;

[0122] Mobile phase: Hexane / EtOH / HAC = 85 / 15 / 0.1 (V / V / V);

[0123] Flow rate: 1.0 ml / min;

[0124] Detection wavelength: UV 254 nm; and

[0125] Column temperature: 35 °C.

[0126] Preparation Method

[0127] In another aspect, the present application relates to a method for preparing the above compound, comprising the following steps:

[0128]

[0129] Wherein, V represents a halogen or a C 1-3 alkylsulfonate group (such as trifluoromethanesulfonate group);

[0130] R 1 、R 2 、R 3 、R 4 、R 5 、ring A and n are all as defined in general formula I.

[0131] In some embodiments, the preparation method comprises the following steps:

[0132] Step 1: The acetate derivative (a) and the phenol derivative (b) undergo a substitution reaction under basic conditions to obtain the intermediate (c); the base is selected from organic bases or inorganic bases, including but not limited to Cs2CO3, K2CO3, t BuOK, NaH, etc.;

[0133] Step 2: The intermediate (c) and the compound (d) undergo a condensation reaction under basic conditions to obtain the intermediate (e); the base is selected from organic bases or inorganic bases, the organic bases include but not limited to sodium tert-butoxide, TEA, DIPEA, Pyridine or DMAP, and the inorganic bases include but not limited to NaH, NaOH, KOH, Na2CO3 or K2CO3;

[0134] Step 3: The intermediate (e) undergoes an ester hydrolysis reaction under acidic or basic conditions to obtain the intermediate (f); the acidic reagents include but not limited to trifluoroacetic acid, hydrochloric acid, etc.; the basic reagents include but not limited to NaOH, KOH, LiOH, etc.;

[0135] Step 4: The intermediate (f) undergoes a hydrogenolysis reaction to obtain the product (Formula (II)); the hydrogenolysis conditions include but not limited to Pd / C and H2, etc.

[0136] Those skilled in the art will understand that the order of each step can be adjusted as needed. For example, hydrogenation or ring formation reactions can be carried out after the removal of the tert-butyl protection. Those skilled in the art will also understand that the tert-butyl group in the ester group of the intermediate c can be replaced with other protecting groups with equivalent functions, which are removed in subsequent steps to finally obtain the acid product, such as benzyl, p-methoxybenzyl, benzyloxycarbonyl, and substituted silyl, etc.

[0137] All of the above steps can be carried out in an organic solvent. The organic solvent can be a commonly used reaction solvent in the art, such as but not limited to N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, saturated hydrocarbons (such as cyclohexane, hexane, etc.), halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), nitriles (such as acetonitrile, etc.) and their mixed solvents, etc.

[0138] In addition, the compound can also be prepared by a variety of methods known to those skilled in the art of organic synthesis. The compound can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof known to those skilled in the art. Preferred methods include (but are not limited to) those described above. The reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the transformation. Those skilled in the art of organic synthesis should understand that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require the following judgment: modifying the order of the synthetic steps or choosing another specific method route relative to one method route to obtain the desired compound.

[0139] It should also be recognized that another major consideration in designing any synthetic route in this field is the correct selection of protecting groups for the reactive functional groups present in the compound. An authoritative description of many alternatives for those trained in the relevant art is Greene et al. (Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience (2006)).

[0140] Unless otherwise specified, the substituents of the compounds in the above routes are as defined herein. Those skilled in the art will understand that one or more steps in the above routes can be omitted according to the structure of the product desired. Those skilled in the art can also appropriately adjust the order of the reaction steps as needed.

[0141] Pharmaceutical Composition and Kit Product

[0142] In another aspect, the present application also provides a pharmaceutical composition, which contains a prophylactically or therapeutically effective amount of the compound described herein or its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, prodrugs or mixtures thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or gaseous preparation.

[0143] The pharmaceutical excipients described in this article refer to the excipients and additives used in the production of drugs and the preparation of prescriptions. They refer to substances that, except for the active ingredients, have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations. Pharmaceutical excipients can be used for shaping, acting as carriers, improving stability, and also have important functions such as solubilization, solubilizing assistance, sustained and controlled release, etc. They are important components that may affect the quality, safety, and effectiveness of drugs. According to their sources, they can be divided into natural products, semi-synthetic products, and fully synthetic products. According to their functions and uses, they can be divided into: solvents, propellants, solubilizers, solubilizing aids, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoaming agents, thickeners, clathrates, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc.; according to their routes of administration, they can be divided into oral, injection, mucosal, transdermal or topical administration, nasal or oral inhalation administration, and ocular administration, etc. Specific pharmaceutical excipients include water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methylcellulose, polyvinylpyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerol, sesame oil, olive oil, soybean oil, etc.

[0144] The pharmaceutical composition can be administered in any form as long as it achieves the prevention, alleviation, prevention, or cure of symptoms in human or animal patients. For example, it can be made into various suitable dosage forms according to the route of administration.

[0145] When administered orally, the pharmaceutical composition can be made into any orally acceptable formulation form, including but not limited to tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, and oral emulsions, etc. Oral suspensions usually use the active ingredient in combination with suitable emulsifiers and suspending agents. Optionally, some sweeteners, fragrances, or colorants can also be added to the above oral formulation forms.

[0146] When administered transdermally or topically, the pharmaceutical composition can be made into appropriate ointment, lotion, or liniment forms, in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used in ointment preparations include but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used in lotions or liniments include but are not limited to: mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, cetyl oleyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0147] The pharmaceutical composition can also be administered in the form of an injection, including injection solutions, sterile powders for injection, and concentrated injection solutions. Among them, the carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.

[0148] The present application also provides a kit product, which contains the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, prodrug, or a mixture thereof, or a pharmaceutical composition, and optionally a drug instruction manual.

[0149] Treatment Method and Use

[0150] Another object of the present application is to provide the use of the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, or a mixture thereof, or the pharmaceutical composition described herein, or the kit product, in the preparation of a drug for preventing or treating a disease or disorder related to peroxisome proliferator-activated receptor (PPAR).

[0151] Another object of the present application is to provide the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, or a mixture thereof, or the pharmaceutical composition described herein, or the kit product, which is used for preventing or treating a disease or disorder related to peroxisome proliferator-activated receptor (PPAR).

[0152] Another object of the present application is to provide a method for preventing or treating a disease or disorder related to peroxisome proliferator-activated receptor (PPAR), the method comprising administering to an individual in need thereof an effective amount of the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, or a mixture thereof, or the pharmaceutical composition described herein, or the kit product.

[0153] Another aspect of the present application provides the use of the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug thereof, or the pharmaceutical composition described herein, or the kit product, in the preparation of a reagent for activating PPAR in cells. In some preferred embodiments, the reagent activates PPAR in cells in vivo, in vitro, or ex vivo.

[0154] Another aspect of the present application provides the compounds described herein or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, or the pharmaceutical compositions described herein, or a kit product, which are used to activate PPAR in cells.

[0155] In some preferred embodiments, the compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, or the pharmaceutical compositions described herein, or a kit product activate PPAR in cells in vivo, in vitro or ex vivo.

[0156] Another aspect of the present application provides a method for activating PPAR in cells, which includes the step of contacting the cells with an effective amount of the compounds described herein or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, or the pharmaceutical compositions described herein, or a kit product.

[0157] In some preferred embodiments, the method is carried out in vivo. In some preferred embodiments, the method is carried out in vitro.

[0158] In one embodiment, the peroxisome proliferator-activated receptor (PPAR) is PPARα and / or PPARδ.

[0159] In one embodiment, the diseases or disorders associated with the peroxisome proliferator-activated receptor (PPAR) are liver diseases and / or bile duct diseases, such as hepatic fibrosis, fatty liver disease, cirrhosis, or, for example, cholangitis.

[0160] In some preferred embodiments, the disease or disorder is non-alcoholic fatty liver disease (NAFLD), biliary cirrhosis, sclerosing cholangitis.

[0161] In some preferred embodiments, the disease or disorder is simple fatty liver (SFL) or non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, primary sclerosing cholangitis.

[0162] In some preferred embodiments, the "cells" are cell lines or cells from a subject. As used herein, the term "effective amount" refers to the amount of a compound that, when administered, will, to some extent, relieve one or more symptoms of the disorder being treated.

[0163] The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus dose can be administered, several divided doses can be administered over time, or the dose can be proportionally decreased or increased as indicated by the exigencies of the treatment situation. It should be noted that the dose values can vary depending on the type and severity of the condition to be alleviated and can include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the administered composition or supervising the administration of the composition. The dosage and dosing regimen of the pharmaceutical composition can be readily determined by a person of ordinary skill in the clinical arts. The compositions or compounds described herein are generally administered once every two days to once every three days, preferably once a day, and the total dose administered is 0.01 to 1000 mg per dose. Generally, the dose of treatment varies depending on considerations such as: the age, sex, and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the degree of tissue damage; the duration of the symptoms; and other variables that can be adjusted by the individual physician. The desired dose can be administered in one or more administrations to obtain the desired result. The pharmaceutical compositions according to the present invention can also be provided in unit dosage form.

[0164] Unless otherwise stated, the term "prevention" refers to a method implemented to block, reduce, inhibit, prevent, and / or delay the occurrence of a disease or disorder or symptom (e.g., a respiratory disease and symptom, an infection, or an autoimmune disease) in an object, and a method of reducing the incidence of infectious diseases in the object.

[0165] As used herein, the term "treatment" refers to a method implemented to obtain a beneficial or desired clinical outcome. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, alleviating symptoms after the object has contracted the disease, reducing the scope of the disease, stabilizing (i.e., no longer deteriorating) the state of the disease, delaying or slowing the development of the disease, improving or alleviating the state of the disease, and alleviating symptoms (whether partial or complete). "Treatment" can also refer to extending the survival period compared to the expected survival period (if not treated).

[0166] As used herein, "individual" or "subject" includes human or non-human animals. Exemplary human individuals include human individuals suffering from a disease (e.g., the diseases described herein) (referred to as patients) or normal individuals. The term "non-human animal" as used herein includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0167] Examples

[0168] Examples and test examples are listed below to further illustrate the present invention in detail, but they do not limit the scope of the present invention. In addition, changes can be made without departing from the scope of the present invention.

[0169] The NMR measurement was performed using a Bruker nuclear magnetic resonance spectrometer, manufacturer: Bruker, model: AVANCE III HD 400.

[0170] The MS measurement was performed using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0171] The preparative high-performance liquid chromatography was carried out using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250×20 mm chromatographic column).

[0172] The thin-layer chromatography purification was carried out using a GF 254 (0.4 - 0.5 nm) silica gel plate produced in Yantai.

[0173] The reaction was monitored by thin-layer chromatography (TLC) or LC-MS. The developing agent systems used include, but are not limited to: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvents was adjusted according to the polarity of the compound, or triethylamine was added for adjustment.

[0174] Column chromatography generally used Qingdao Ocean silica gel of 200 - 300 mesh as the stationary phase. The eluent systems include, but are not limited to, dichloromethane and methanol systems and n-hexane and ethyl acetate systems. The volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of triethylamine could also be added for adjustment.

[0175] If not otherwise specified in the examples, the reaction temperature was room temperature (20°C - 30°C).

[0176] The reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company, or Teb Chemical.

[0177] The abbreviations used herein have the following meanings:

[0178] Abbreviation Meaning Abbreviation Meaning DMP Dess-Martin Oxidant <![CDATA[Na2SO4]]> Sodium Sulfate Oxone Potassium Monopersulfate <![CDATA[Na2SO3]]> Sodium Sulfite IBX 2-Iodoxybenzoic Acid HCl Hydrogen Chloride Jones Jones Oxidant TFA Trifluoroacetic Acid PDC Pyridinium Dichromate <![CDATA[CF3SO3H]]> Trifluoromethanesulfonic Acid PCC Pyridinium Chlorochromate HCOOH Formic Acid TEA Triethylamine MeOH Methanol DIPEA N,N-Diisopropylethylamine EtOH Ethanol DMAP 4-Dimethylaminopyridine MeCN Acetonitrile Pyridine Pyridine <![CDATA[Et2O]]> Diethyl Ether NaH Sodium Hydride THF Tetrahydrofuran NaOH Sodium Hydroxide Acetone Acetone KOH Potassium Hydroxide DCM Dichloromethane LiOH Lithium Hydroxide DMF N,N-Dimethylformamide <![CDATA[Na2CO3]]> Sodium Carbonate NMP N-Methylpyrrolidone <![CDATA[Potassium carbonate]]> Potassium Carbonate DMSO Dimethyl Sulfoxide <![CDATA[Cs2CO3]]> Cesium Carbonate EtOAc Ethyl Acetate NaOMe Sodium Methoxide LC-MS Liquid Chromatography-Mass Spectrometry <![CDATA t BuOK]]> Potassium tert-Butoxide NMR Nuclear Magnetic Resonance LDA Lithium Diisopropylamide HPLC High Performance Liquid Chromatography <![CDATA[H2]]> Hydrogen TLC Thin Layer Chromatography Pd / C Palladium on Carbon

[0179] Example 1: Preparation of tert-butyl 2-(4-formyl-2,6-dimethylphenoxy)-2-methylpropionate (Int 1)

[0180]

[0181] Dissolve SM1 3,5-dimethyl-4-hydroxybenzaldehyde (100 g, 0.67 mol) in DMF (800 mL), add cesium carbonate (543 g, 1.67 mol), heat the mixture to 100 °C and react for 30 min. Then, add tert-butyl 2-bromoisobutyrate (297 g, 1.33 mol) dropwise to the system. After the addition is complete, heat the mixture to 120 °C and react for 8 h. Monitor the reaction by LC-MS and when there is no tendency for further conversion. Pour the reaction solution into ice water, separate the layers, and collect the aqueous phase. Extract the aqueous phase with ethyl acetate, combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain compound Int 1 (31 g). MS m / z (ESI): 293.0 [M+H] + 。

[0182] Example 2:

[0183] Preparation of 2-(4-(3-hydroxy-3-(2-methoxyquinolin-3-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (TM2)

[0184]

[0185] First step: Preparation of compound 2-2

[0186] Dissolve compound 2-1 (300 mg, 1.46 mmol) in methanol (5 mL), then add sodium methoxide (5 M) (1.46 mL, 7.30 mmol). Monitor the reaction by LC-MS until completion. Pour the reaction solution into ice water, adjust the pH to 2 with 3N HCl aqueous solution, extract with ethyl acetate, and combine the organic phases. Wash the organic phase once with saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate, and purify by silica gel column chromatography to obtain the target product (2-2) (270 mg).

[0187] MS m / z (ESI): 202.2 [M+H] + 。

[0188] Second step: Preparation of compound 2-3

[0189] Dissolve compound 2-2 (150 mg, 0.74 mmol) and Int 1 (216 mg, 0.74 mmol) in ethanol (20 mL), cool the mixture in an ice-water bath for 10 min, add 10% NaOH (0.35 mL), and react for 16 h. Monitor the reaction by LC-MS until there is no tendency for further conversion. Add water and extract with ethyl acetate, combine the organic phases. Wash the organic phase once with saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate, and purify by silica gel column chromatography to obtain the target product (2-3) (160 mg).

[0190] MS m / z(ESI):476.3[M+H] + 。

[0191] Step 3: Preparation of Compound 2-4

[0192] Dissolve Compound 2-3 (138 mg, 0.29 mmol) in DCM (4.5 mL), cool it in an ice-water bath for 10 min, add dropwise TFA (1.5 mL), react for 1 h, and monitor the completion of the reaction by LC-MS. Concentrate the reaction solution and purify it by column chromatography to obtain the target product (2-4) (67 mg).

[0193] MS m / z(ESI):420.2[M+H] + 。

[0194] Step 4: Preparation of Compound TM2

[0195] Add Compound 2-4 (4.5 g, 10.73 mmol) to MeOH (45 mL), add 10% Pd / C (450 mg) under stirring, replace the reaction system with hydrogen three times, and react at room temperature for 16 h. Monitor the completion of the reaction by LC-MS. Filter the reaction solution through diatomaceous earth, concentrate the filtrate, and purify it through a silica gel column (eluent system: DCM / MeOH = 0 - 5%) and preparative HPLC (mobile phase: formic acid, acetonitrile / water) to obtain Compound TM2 (1.4 g).

[0196] MS m / z(ESI):424.1[M+H] + .

[0197] 1 H NMR(400MHz,DMSO-d6)δ12.79(s,1H),8.25(s,1H),7.90(d,J=7.2Hz,1H),7.75(d,J=8.4Hz,1H),7.61(t,J=8.0Hz,1H),7.41(t,J=8.0Hz,1H),6.80(s,2H),5.40(br,1H),4.87–4.81(m,1H),3.97(s,3H),2.70–2.55(m,2H),2.10(s,6H),2.07–1.97(m,1H),1.85–1.73(m,1H),1.32(s,6H).

[0198] Example 3: Preparation of (S)-2-(4-(3-hydroxy-3-(2-methoxyquinolin-3-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid and (R)-2-(4-(3-hydroxy-3-(2-methoxyquinolin-3-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid

[0199]

[0200] TM2 (35 g) was synthesized in the same manner as in Example 2, and a pair of enantiomers of compound TM2, TM2-1 (14.4 g) and TM2-2 (14.8 g), were obtained by chiral resolution. The resolution conditions were as follows:

[0201] Column: CHIRALPAK IC (IG00CD-KJ016), column size: 0.46 cm I.D. × 15 cm L, injection volume: 1 μL, mobile phase: Hexane / EtOH / HAC = 85 / 15 / 0.1 (V / V / V), flow rate: 1.0 mL / min, detection wavelength: UV254 nm, column temperature: 35 °C.

[0202] The retention time of TM2-1 was (t1 = 3.466 min), and the retention time of TM2-2 was (t2 = 5.777 min).

[0203] The specific rotation detection conditions of TM2-1: detection temperature: 20 °C, detection wavelength 589.3 nm, [α]: +9.7°, (methanol, C = 100 mg / mL).

[0204] The specific rotation detection conditions of TM2-2: detection temperature: 20 °C, detection wavelength 589.3 nm, [α]: -9.5°, (methanol, C = 100 mg / mL).

[0205] TM2-1:

[0206] MS m / z (ESI): 424.1 [M+H] + .

[0207] 1 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.25 (s, 1H), 7.90 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.45 - 7.38 (m, 1H), 6.80 (s, 2H), 5.40 (d, J = 4.4 Hz, 1H), 4.90–4.81 (m, 1H), 3.98 (s, 3H), 2.70–2.55 (m, 2H), 2.10 (s, 6H), 2.07–1.97 (m, 1H), 1.85–1.73 (m, 1H), 1.32 (s, 6H).

[0208] TM2-2:

[0209] MS m / z (ESI): 424.1 [M+H]+ .

[0210] 1 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.25 (s, 1H), 7.90 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.45 - 7.38 (m, 1H), 6.80 (s, 2H), 5.40 (d, J = 4.0 Hz, 1H), 4.87–4.81 (m, 1H), 3.98 (s, 3H), 2.70–2.55 (m, 2H), 2.10 (s, 6H), 2.07–1.97 (m, 1H), 1.85–1.73 (m, 1H), 1.32 (s, 6H).

[0211] Pharmacological tests

[0212] Experimental Example 1: Activation test of the compound on PPARα, δ and γ at the cellular level

[0213] Cells: Genetically engineered from Chinese hamster ovary cells CHO-K1, a total of 3 strains, namely CHO-K1 PPARα Protein Interaction Cell Line, CHO-K1PPARδ Protein Interaction Cell Line and CHO-K1 PPARγ Protein Interaction Cell Line, sourced from DiscoverX.

[0214] Detection kit: Detection Kit, sourced from DiscoverX.

[0215] 1. Test method

[0216] Adopt The cell assay method of protein interaction to test the nuclear receptor agonist activities of PPARα, δ and γ.

[0217] 1) Cell culture: Resuscitate 3 different cell lines of CHO-K1 PPARα, δ, γ Protein Interaction respectively and culture them overnight. Digest and count the cells, take 20 μL of cell suspension and add it to a 384-well white microplate, and culture it in a medium containing charcoal-stripped dextran serum at 37 °C and 5% CO2.

[0218] 2) Compound Incubation: Add 5 μL of 5× test compounds at different concentrations to the cells in a 384-well plate, so that the final concentrations are 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM (corresponding to compound GFT505, TM2), or so that the final concentrations are 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.123 μM, 0.041 μM, 0.014 μM, 0.0046 μM, 0.0015 μM, 0.0005 μM (corresponding to compound TM2-2). The final concentration of DMSO is 1%. Incubate at 37°C under 5% CO₂ conditions.

[0219] 3) Signal Detection: After incubating the test compounds with the cells for 6 h, add 12.5 μL (50% v / v) of PathHunter detection reagent. After incubating at room temperature for 1 h, use a PerkinElmer Envision TM multifunctional microplate reader to detect the chemiluminescence unit value (RLU).

[0220] 4) Data Analysis: Use CBIS software (ChemInnovation, CA) for data analysis. Use the following formula to calculate the activity percentage of the compound at different concentrations: Activity percentage % = (RLU of test sample - RLU of vehicle control) / (RLU of maximum activation - RLU of vehicle control) × 100%. Calculate the EC 50 value of the activity of the compound at different concentrations against different targets of PPARα, δ, γ by curve fitting.

[0221] 2. Test Results

[0222] The agonistic activities of the compounds against the three nuclear receptors PPARα, δ, γ were tested, and the determination results are shown in Tables 1 - 3.

[0223] Table 1 Agonistic Activity of Compounds against PPARα

[0224] Compound Number <![CDATA[EC 50 (μM)]]> GFT505 0.317 TM2 0.018 TM2-2 0.012

[0225] As shown in the data of Table 1, compared with GFT505, compounds TM2 and TM2-2 have stronger agonistic activities against PPARα in in vitro cell activity assays.

[0226] Table 2 Agonistic Activity of Compounds against PPARδ

[0227] Compound Number <![CDATA[EC 50 (μM)]]> GFT505 0.111 TM2 0.126 TM2-2 0.092

[0228] Data in Table 2 show that compounds TM2, TM2-2, and GFT505 have comparable agonist activities against PPARδ in in vitro cell activity assays.

[0229] Table 3 Agonist Activities of Compounds against PPARγ

[0230] Compound Number <![CDATA[EC 50 (μM) <!-- 19 -->]]> GFT505 0.594 TM2 0.237 TM2-2 0.168

[0231] Data in Table 3 show that compared with GFT505, the agonist activities of compound TM2 and its isomer TM2-2 against PPARγ are both increased in in vitro cell activity assays, and the increase in the agonist activity of TM2-2 is more significant.

[0232] In summary, in in vitro cell activity assays, compounds TM2 and TM2-2 have agonist activities against PPARα, δ, and γ, among which they have stronger agonist activities against PPARα and better selectivity for PPARα compared with PPARδ and PPARγ. Compared with GFT505, the agonist activity of compound TM2 against PPARα is increased by 17 times, and the affinity of TM2-2 for PPARα is increased by 26 times; the agonist activities of compounds TM2 and TM2-2 against PPARδ are comparable to that of GFT505; the agonist activity of compound TM2 against PPARγ is comparable to that of GFT505, and the agonist activity of compound TM2-2 is stronger than that of GFT505.

[0233] Note: GFT505 is a PPAR receptor agonist drug under clinical research. Its structure is shown as follows and is synthesized according to the prior art:

[0234]

[0235] Experimental Example 2: Study on the Effect of Compounds on hERG Current

[0236] In this experiment, HEK293T cells stably transfected with the hERG gene were used to study the effect of compounds on hERG channel current by using the manual patch-clamp whole-cell patch-clamp technique, calculating the concentration-effect curve, and evaluating the risk of ventricular repolarization toxicity.

[0237] 1. Experimental Method

[0238] 1) Cell culture: After cell resuscitation and subculture, the cells were seeded in a 24-well plate (pre-placed with 12 mm round coverslips) 4 - 8 hours before the experiment for cell seeding. The round coverslips were taken out before detection, washed with extracellular fluid, and then soaked for testing.

[0239] 2) Voltage stimulation protocol and current recording: In the whole-cell recording mode, each voltage stimulation consists of the following 5 phases: Phase A, maintaining the cell membrane clamping potential at -80 mV for 0.5 s; Phase B, applying a repolarizing voltage of -50 mV to the cell for baseline tail current measurement for 0.5 s; Phase C, applying a depolarizing voltage of +50 mV to the cell for 2.5 s; Phase D, repolarizing to -50 mV to elicit the hERG tail current for 4 s; Phase E, restoring the clamping potential to -80 mV for 0.5 s. The entire stimulation process is 8 s, and after each voltage stimulation is completed, it is repeated at an interval of 2 s, that is, each stimulation cycle is 10 s.

[0240] 3) Drug administration process: For compound administration, a perfusion drug delivery system (performed at room temperature) is used. The negative control (extracellular fluid containing 0.1% DMSO), compound solutions with concentrations of 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM are added to the 1-6th sampling channels respectively. The liquids in the 1-6th channels are sequentially applied to the cells by gravity perfusion. When detecting positive drugs, extracellular fluid containing 0.3% DMSO, Terfenadine test solutions with concentrations of 50 nM, 100 nM, 200 nM, 400 nM, and 800 nM are added to the 1-6th sampling channels respectively. The hERG tail current of the negative control is stably recorded in the extracellular fluid for no less than 3 min. Perfuse the compound or positive control. When the change in the amplitude of the hERG tail current < 5%, it is considered that the drug effect has reached a steady state. If the current does not reach a steady state within 6 minutes, the detection of the compound at this concentration is also terminated.

[0241] 4) Data acquisition and analysis: Patchmaster (version: 2X65) software is used for data acquisition and analysis, and then Igor Pro (version: 6.3.7.2) and EXCEL2007 are used for analysis. The calculation method of the tail current value is the peak current value in Section D minus the average current value in Section B. The sweep tail current with a steady state current before adding the compound is selected as the control current. The sweep tail current value with a steady state current after adding the compound is selected as the inhibitory current.

[0242] The inhibition rate of the test compound on the hERG current is calculated according to the following equation:

[0243] Inhibition rate = (1 - inhibitory current / control current) × 100%

[0244] After obtaining the inhibition rates (mean ± standard deviation) of multiple concentrations of the test compound on the hERG current according to the above calculation method, GraphPad Prism5 (version: 5.01) software is used to fit the data to obtain the IC 50 value.

[0245] 2. Test results

[0246] Under the conditions of this experiment, the IC 50 of compound TM2 against hERG current was 121.03 ± 22.41 μM, indicating that the compound had no inhibitory effect on the hERG channel within the test concentration range.

[0247] Experimental Example 3: Bacterial Reverse Mutation Test of Compound

[0248] Under the conditions of adding and not adding an in vitro metabolic activation system, the mutagenicity of the compound was detected using 5 histidine-auxotrophic Salmonella typhimurium mutant strains (TA97a, TA98, TA100, TA102, and TA1535) to predict its genetic hazard and the possibility of potential carcinogenic effects.

[0249] 1. Test method

[0250] 1) Test operation: Five Salmonella typhimurium mutant strains, namely TA97a, TA98, TA100, TA102, and TA1535, were selected as standard test strains. The plate incorporation method was used in the test, which was carried out under two treatment conditions: adding an in vitro metabolic activation system (+S9) and not adding an in vitro metabolic activation system (-S9). According to the results of the preliminary test, DMSO was used as the solvent in this test. Under the two treatment conditions of adding or not adding an in vitro metabolic activation system, 5 concentration groups of the compound were set in each test strain, namely 5000 μg / plate, 2000 μg / plate, 800 μg / plate, 320 μg / plate, and 128 μg / plate. At the same time, a solvent control group and a positive control group were set in parallel. Three parallel plates were set for each concentration group (including the solvent control and the positive control).

[0251] 2) Result determination: If, for at least one of the test strains, when adding or not adding an in vitro metabolic activation system, the number of revertant colonies in the test article group is compared with the number of revertant colonies in the corresponding solvent control group and exceeds a certain range (that is, the average number of revertant colonies in the test article group of the test strain TA1535 is equal to or greater than 3 times the average value of the solvent control group, and the average number of revertant colonies in the test article group of other test strains is equal to or greater than 2 times the average value of the solvent control group), and there is a concentration-response relationship, or there is a significant and reproducible increase in the number of revertant colonies at a certain test point (strain or concentration), the test result can be determined as positive.

[0252] If the increase in the number of revertant colonies does not reach more than the threshold (2 times or 3 times), but there is a concentration-response relationship. Or if the increase in the number of revertant colonies is equal to or greater than their respective thresholds (2 times or 3 times) but there is no concentration-response relationship. The test results can both be determined as suspicious results.

[0253] 3) Data processing and statistical analysis: The mean and standard deviation of the number of revertant colonies in each group were calculated using Microsoft Excel 2013, and the ratio of the number of revertant colonies in each group to the corresponding solvent control group was calculated.

[0254] 2. Test results

[0255] Under the conditions of this experiment, in the two treatment conditions of adding or not adding an in vitro metabolic activation system, the compound TM2 at 5000, 2000, 800, 320, and 128 μg / plate was not mutagenic to all test strains, that is, the results of the Ames test were negative.

[0256] Experimental Example 4: In vitro mammalian cell chromosome aberration test of the compound

[0257] Using Chinese hamster lung fibroblasts (CHL) cultured in vitro, it was detected whether the compound could cause chromosome aberrations in vitro mammalian cells to evaluate the mutagenic potential of the test article.

[0258] 1. Test method

[0259] 1) Test operation: In this test, DMSO was used as the solvent control for the test. The positive controls and their use concentrations were ethyl methanesulfonate at 1000 μg / mL (-S9, 3 h), 500 μg / mL (-S9, 24 h), and cyclophosphamide for injection at 5 μg / mL (+S9, 3 h). The metabolic activation system was a liver homogenate of SD rats (S9) induced by a combination of phenobarbital and β-naphthoflavone. The test was set with three treatment conditions, namely adding an in vitro metabolic activation system for 3 hours, not adding an in vitro metabolic activation system for 3 hours, and not adding an in vitro metabolic activation system for 24 hours. According to the results of the preliminary test, the highest concentration of the compound under these 3 treatment conditions was set at 250 μg / mL. For each treatment condition, the compound was set at 5 concentrations, namely 250 μg / mL, 100 μg / mL, 40 μg / mL, 16 μg / mL, and 6.4 μg / mL; the solvent control and positive control groups were set in parallel, and 2 parallel cell cultures were set for each concentration. Colchicine (final concentration 0.1 μg / mL) was used for 2 hours before harvesting to block the cells at the metaphase. The cells were harvested 24 hours after dosing, and cell counting, cytotoxicity analysis, and slide preparation were performed. According to the results of cytotoxicity analysis, 3 concentrations, including the solvent control, were selected for microscopy in each treatment condition, and at least 300 metaphase cells were observed; the positive control was examined by microscopy, and at least 100 metaphase cells were observed to analyze chromosome aberrations.

[0260] 2) Result evaluation: The number of chromosome structural aberrations induced by the compound showed a statistically significant increase (P<0.05), and there was a concentration-effect correlation; or at any concentration of the compound, the number of chromosome structural aberrations showed a statistically significant increase (P<0.05), and it was reproducible. Either of the above two situations can be judged as a positive result. If the chromosome aberration cell rate of any compound concentration group did not increase significantly compared with the vehicle control group, the compound can be considered negative.

[0261] 3) Data processing and statistical analysis: ① Data calculation: The total number of structural aberrations of cells in each culture flask should be calculated according to the following classification: the total number of counted cells, the total number of aberrant cells, the total number of aberrant chromosomes, and the total number of gaps; ② Statistical processing: Microsoft Excel 2013 and SPSS 13.0 software were used for calculation and analysis. The formation rate of chromosome aberration cells in the dosing group (including the positive control group) and the vehicle control group was compared. The Fisher Exact probability method was used to identify significant differences. The positive control group and the vehicle control group were compared pairwise. When P<0.05, the difference was considered significant. First, multiple comparisons were made between the compound group and the vehicle control group. If P≥0.05, the difference was considered not significant; if P<0.05, pairwise comparisons were continued between each concentration of the test article and the vehicle control group. The obtained P value was corrected by the Bonferroni method (that is, the P value was multiplied by the number of samples. The number of samples in this experiment was 3). When the corrected P value <0.05, the difference was considered significant.

[0262] 2. Test results

[0263] Under the conditions of this experiment, the compound TM2 at 40, 100, and 250 μg / mL did not cause a significant increase in the chromosome structural aberration rate of CHL cells after exposure for about 3 and 24 hours without adding an in vitro metabolic activation system and after exposure for about 3 hours with an added in vitro metabolic activation system. It has no mutagenicity to CHL mammalian cells cultured in vitro. The result of the chromosome aberration test was negative.

[0264] Except those described herein, various modifications of the present invention will be apparent to those skilled in the art in light of the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other publications) are incorporated herein by reference in their entirety.

Claims

1. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of general formula (II): Wherein: R 1 、R 2 、R 3 、R 4 Each independently selected from C 1-6 alkyl; R 5 each independently selected from H, C 1-6 alkoxy and C 1-6 alkylthio; Ring A is selected from: n is any integer from 0 to 6.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, R 1 、R 2 、R 3 、R 4 Each independently selected from methyl, ethyl, n-propyl, isopropyl; R 5 each independently selected from H, C 1-4 alkoxy and C 1-4 alkylthio group.

3. The compound of claim 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, R 1 、R 2 、R 3 and R 4 are methyl; each R 5 is independently selected from H, methoxy and methylthio.

4. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, n is 0, 1, 2 or 3.

5. The compound of claim 4 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, n is 1 or 2.

6. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, Selected from: Each R 5 as defined in any one of claims 1 to 3.

7. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, Selected from:

8. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from:

9. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from:

10. The stereoisomers of the following compounds:

11. The stereoisomer according to claim 10, wherein the optical rotation direction detected under the following optical rotation detection conditions is left-handed: detection temperature: 20 °C, detection wavelength 589.3 nm, solvent is methanol, and concentration is 100 mg / mL.

12. The stereoisomer according to claim 11, wherein its specific rotation [α] D 20= -9.5° ± 1°.

13. The stereoisomer according to claim 11, having a specific rotation [α] D 20 = -9.5° ± 0.9°, -9.5° ± 0.8°, -9.5° ± 0.7°, -9.5° ± 0.6°, -9.5° ± 0.5°, -9.5° ± 0.4°, -9.5° ± 0.3°, -9.5° ± 0.2° or -9.5° ± 0.1°.

14. The stereoisomer according to any one of claims 11 - 13, having a retention time of 5.8 min ± 1 min under the following liquid phase conditions: Column: CHIRALPAK IC (IG00CD - KJ016); Column size: 0.46 cm I.D. × 15 cm L; Sample injection volume: 1 μL; Mobile phase: Hexane / EtOH / HAC = 85 / 15 / 0.1 (V / V / V); Flow rate: 1.0 ml / min; Detection wavelength: UV 254 nm; and Column temperature: 35°C.

15. The stereoisomer according to claim 14, having a retention time of 5.8 min ± 0.9 min, 5.8 min ± 0.8 min, 5.8 min ± 0.7 min, 5.8 min ± 0.6 min, 5.8 min ± 0.5 min, 5.8 min ± 0.4 min, 5.8 min ± 0.3 min, 5.8 min ± 0.2 min or 5.8 min ± 0.1 min under the liquid phase conditions.

16. The stereoisomer according to claim 10, having a dextrorotatory direction detected under the following specific rotation detection conditions: Detection temperature: 20°C, detection wavelength 589.3 nm, solvent is methanol, and concentration is 100 mg / mL.

17. The stereoisomer according to claim 16, having a specific rotation [α] D 20 = +9.7° ± 1°.

18. The stereoisomer according to claim 17, having a specific rotation [α] D 20 = +9.7° ± 0.9°, +9.7° ± 0.8°, +9.7° ± 0.7°, +9.7° ± 0.6°, +9.7° ± 0.5°, +9.7° ± 0.4°, +9.7° ± 0.3°, +9.7° ± 0.2° or +9.7° ± 0.1°.

19. The stereoisomer according to any one of claims 16 - 18, having a retention time of 3.5 min ± 1 min under the following liquid phase conditions: Chromatographic column: CHIRALPAK IC (IG00CD - KJ016); Chromatographic column size: 0.46 cm I.D. × 15 cm L; Sample injection volume: 1 μL; Mobile phase: Hexane / EtOH / HAC = 85 / 15 / 0.1 (V / V / V); Flow rate: 1.0 ml / min; Detection wavelength: UV 254 nm; and Column temperature: 35 °C.

20. The stereoisomer according to claim 19, having a retention time of 3.5 min ± 0.9 min, 3.5 min ± 0.8 min, 3.5 min ± 0.7 min, 3.5 min ± 0.6 min, 3.5 min ± 0.5 min, 3.5 min ± 0.4 min, 3.5 min ± 0.3 min, 3.5 min ± 0.2 min or 3.5 min ± 0.1 min under the liquid phase conditions.

21. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

22. A kit product containing the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 21, and optionally a package insert.

23. Use of the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, stereoisomer thereof, the pharmaceutical composition of claim 21, or the kit product of claim 22 in the manufacture of a medicament for the prophylaxis or treatment of a PPAR - related disease or disorder.

24. The use according to claim 23, wherein the PPAR is PPARα and / or PPARδ.

25. The use according to claim 23, wherein the disease or disorder is a liver disease and / or a bile duct disease.

26. The use according to claim 23, wherein the disease or disorder is selected from hepatic fibrosis, fatty liver disease, cirrhosis, cholangitis.

27. The use according to claim 23, wherein the disease or disorder is non - alcoholic fatty liver disease, biliary cirrhosis, sclerosing cholangitis.

28. The use according to claim 23, wherein the disease or disorder is simple fatty liver or non-alcoholic steatohepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

29. A method for preparing a compound of formula (II), comprising the following steps: Wherein, V is a halogen or an optionally halogen-substituted C 1-3 alkylsulfonate group; R 1 , R 2 , R 3 , R 4 , R 5 , ring A and n are as defined in any one of claims 1-9.

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